DESCRIPTION (provided by candidate): Although Alzheimer's, Parkinson's, and Huntington's diseases have certain distinct clinical characteristics, the single protein Uch-L1 has been implicated in all three disorders. Furthermore, a common natural variant of Uch-L1 (S18Y) has been shown to provide protection from all three of these diseases. The only visible difference between Uch-L1 S18Y and the wild-type protein is that the neuroprotective variant crystallizes as a dimer, whereas the wild-type protein appears as a monomer. Uch-L1 protein makes up a substantial proportion (up to 2%) of soluble protein in the central nervous system. However, the role of Uch- L1 protein in either normal or diseased neuronal tissue is unknown. The dimerization of Uch-L1 protein will be explored in detail, and small molecules will be experimentally screened for their ability to stabilize dimeric Uch-L1. Uch-L1 dimerization will be exploited as a method to protect against neurodegenerative diseases;successful small molecules will be converted into lead compounds for oral therapeutics that can protect at-risk individuals from Parkinson's Disease. Additionally, three proteins have been found to interact with Uch-L1. Their identities will be determined and used to make new hypotheses about the role of Uch-L1 in healthy neuronal tissue. Uch-L1 will be assayed for ubiquitin hydrolase activity on any monoubiquitinated proteins that interact with it. Lastly, an irreversible inhibitor of cysteine proteases will be co-crystallized with Uch-L1 in an effort to trap and observe an active protein conformation. Uch-L1 protein is a uniquely valuable target for drug development because a common natural variant is known to protect against Parkinson's, Alzheimer's, and Huntington's diseases. However, the functions of Uch-L1 in disease development or in healthy tissue are unknown. This proposal seeks to understand the normal roles of Uch-L1 protein and to find drug-like molecules that can stabilize neuroprotective Uch-L1 and protect individuals from development of neurodegenerative diseases.